The use of catheters to deliver therapeutic fluids into the tissues of mammals is well known in the field of medicine. Catheters are used to deliver various therapeutic fluids to various tissues, including the delivery of pain medication to the spinal cord and brain, the delivery of anti-neoplastic agents to the brain, liver, and other tissues, and the delivery of various bioactive agents directly into the vasculature. The use of catheters to deliver therapeutic fluids directly into a target tissue provides several benefits over conventional routes of administration, including the elimination of gastric metabolism that occurs via oral administration. Another major benefit includes the use of less bioactive agent and the subsequent sparing of non-target tissues when the bioactive agents have undesirable side effects, such as highly toxic anti-neoplastic agents or highly specific proteins, growth factors, and gene therapy agents.
Some bioactive agents have great difficulty crossing the blood-brain barrier, requiring much higher levels to be obtained in the blood to achieve effective therapeutic concentrations in the brain. The use of drug delivery catheters implanted directly into the brain tissue has opened up the possibilities of using therapeutic agents for many neurological diseases and conditions that were previously untreatable.
Convection enhanced delivery (CED) utilizes fine intracranial catheters and low infusion rates of continuous injection under positive pressure to impart drugs directly into the extracellular space of the brain. First introduced by the National Institutes of Health in the 1990's, this technique has only recently been used for the treatment of brain cancer, and allows for a focused delivery of drugs to a specific target area. CED does not depend on diffusion, but relies on catheter design and a precisely controlled infusion rate to create a pressure gradient, along which a therapeutic agent passes directly into the extracellular space. This allows for a controlled homogenous distribution even for relatively large molecules such as proteins over large volumes of the brain and spinal cord.
Direct infusion into the brain by CED faces a number of challenges however, the most prominent being unpredictability of the distribution of the drug. The greatest contributor to the unpredictability is backflow of the infused agent along the catheter's insertion track. As the flow of infusate permeates the surrounding tissue, the tissue surrounding the catheter gradually experiences “creep” phenomena, whereby the fluid slowly flows alongside the exterior of the catheter, displacing the surrounding tissue until eventually the surrounding tissue no longer seals the catheter track and fluid reaches the entrance point of the catheter into the tissue. Upon reaching the entrance point, this fluid path alongside the catheter then becomes the path of least resistance and thus the primary path of fluid flow, creating an undesirable drug distribution to adjacent non-target tissues. For a discussion of CED see for example Morrison, et al., in Am J Physiol. 1999 October; 277 (4 Pt 2):R1218-29.
Others have attempted to overcome this limitation by incorporating various modifications to the catheter size, design, and materials. For example Krauze, et al., describe the use of a step-design cannula to limit or prevent backflow (J. Neurosurg 103:923-929, 2005). In PCT application publication WO 2008/020241A2 Gill, et al., describe the use of a stiff catheter shaft material to prevent vibrations and movement, and thus prevent backflow. In USPAP 2007/0276340A1 Poston, et al., describe the use of inflatable stents on the catheter shaft to create a seal in the tissue.
These mechanical modifications do not completely prevent backflow and also add complexity and cost to the catheter. Thus there is an ongoing need for a method to safely deliver a therapeutic fluid into the tissue of a mammal.